1. Field of the Invention
This invention relates to a novel class of antibiotics, designated by the present inventors as bravomicins, which may be obtained by cultivation of a strain of Micromonospora polytrota. The present invention also provides O- and N-acylated derivatives of the novel bravomicins. The compounds of the present invention are useful in the treatment of bacterial diseases.
2. Background Art
Emergence of bacterial resistance to a number of antimicrobial agents such as beta-lactam antibiotics, macrolides, quinolones, and vancomycin is becoming a major worldwide health problem. (Cohen, M. L. Antimicrobial resistance: prognosis for public health. Trends Microbiol. 1994, 2, 422-425). The most significant problem in clinical practice is the increase in the isolation of methicillin-resistant Staphylococcus aureus (MRSA) strains. In the United States, by the early 1990s MRSA was detected in 20-40% of all S. aureus hospital isolates reported to the National Nosocomial Infections Surveillance (NNIS) System and is also a major problem in long-term care facilities. Other than the United States, the occurrence of epidemic strains of MRSA has also been reported in many countries such as Argentina, Australia, Belgium, Canada, Denmark, France, Germany, Greece, Hong Kong, Italy, Japan Malaysia, Netherlands, New Zealand, Portugal, Spain, Sweden, Taiwan, and the United Kingdom. In addition to resistance to beta-lactam antibiotics, multiply resistant MRSA are also resistant to macrolides, tetracyclines, aminoglycosides, and fluoroquinolones. At present, the only effective treatment for multiply resistant MRSA infections is vancomycin. However, the minimum inhibitory concentration (MIC) for vancomycin against some MRSA isolates has been increasing recently, leading to a situation where standard doses of vancomycin may not be effective for severe infections. (Major Unmet Needs in Bacterial Infection Therapy. Infectious Disease, A Pharmacor Service, August, 1992.)
Enterococci are another group of bacteria which are generally resistant to antibiotics such as penicillins, cephalosporins, and aminoglycosides. Current treatment for enterococcal infection is the use either of a combination of two antibiotics or of vancomycin alone. However, with the recent increased use of vancomycin in MRSA infections and colitis due to Clostridium difficile, multiply resistant Enterococcus faecium has emerged. In a recent report to the Center of Disease Control's NNIS, the percentage of nosocomial enterococci resistant to vancomycin increased from 0.3% in 1989 to 7.9% in 1993. Because of the fact that only a few drugs can be used effectively to treat enterococcal infections, treatment options for patients infected with vancomycin-resistant enterococci are very limited. Furthermore, the Gram-negative organisms such as Pseudomonas, Klebsiella, Proteus, and Enterobacter species were the important antibiotic resistant pathogens in the 1970s; they remain a highly risky problem in some hospitals today.
Apart from the nosocomial pathogens described above, the resistance of the important community-acquired pathogen Streptococcus pneumoniae to penicillin and other antibacterials is becoming a worldwide problem. Multidrug-resistant strains of Mycobacterium tuberculosis have emerged in several countries including the United States. The emergence and spread of resistant nosocomial and community-acquired pathogens is generating a great threat to public health worldwide. There is an urgent need to discover new agents to treat patients infected with these multidrug-resistant bacteria.
The present invention provides what appears to be a new class of antibiotics. They were produced by fermentation of a strain of Micromonospora polytrota previously disclosed in U.S. Pat. No. 4,307,085 as being used to prepare a different class of antibiotics described as the AR-5 antibiotic complex.